The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance 1 1Edited by R. Huber

Gordón, E.; Mouz, Nicolas; Duee, E.; Dideberg, Otto

doi:10.1006/jmbi.2000.3740

Cited by 202 publications

(252 citation statements)

References 42 publications

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“…perimentally, has been predicted to interact with cell wall peptidoglycan based on structural analysis of Streptococcus pneumoniae Pbp2X, which contains two PASTA domains, bound to a ␤-lactam antibiotic (Gordon et al 2000;Yeats et al 2002). In the context of our experimental data, these conserved features strongly support a commonality of function of PknB-like STPKs in regulating cell shape in a broad range of gram-positive bacteria.…”

Section: Discussionsupporting

confidence: 61%

The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape

Kang¹,

Abbott²,

Park³

et al. 2005

Genes Dev.

356

470

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The Mycobacterium tuberculosis genome contains 11 serine/threonine kinase genes including two, pknA and pknB, that are part of an operon encoding genes involved in cell shape control and cell wall synthesis. Here we demonstrate that pknA and pknB are predominantly expressed during exponential growth, and that overexpression of these kinases slows growth and alters cell morphology. We determined the preferred substrate motifs of PknA and PknB, and identified three in vivo substrates of these kinases: PknB; Wag31, an ortholog of the cell division protein DivIVA; and Rv1422, a conserved protein of unknown function. Expression of different alleles of wag31 in vivo alters cell shape, in a manner dependent on the phosphoacceptor residue in the protein produced. Partial depletion of pknA or pknB results in narrow, elongated cells. These data indicate that signal transduction mediated by these kinases is a novel mechanism for the regulation of cell shape in mycobacteria, one that may be conserved among gram-positive bacteria.[Keywords: Kinase; DivIVA; peptide library screen; mycobacteria] Supplemental material is available at http://www.genesdev.org.

show abstract

Section: Discussionsupporting

confidence: 61%

The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape

Kang¹,

Abbott²,

Park³

et al. 2005

Genes Dev.

356

470

View full text Add to dashboard Cite

show abstract

“…Not surprisingly, these functionalities find well-conserved complements in the AmpC active site that are readily apparent in the consensus overlay of ligand complexes ( Figure 5). As observed in every serine -lactam-recognizing enzyme studied, 4,30,[36][37][38][39][40][41] there is a well-conserved oxyanion 35 or electrophilic 6 hole that recognizes the carbonyl oxygen of the lactam acyl adduct, made up of the main chain atoms of Ser64 and Ala318 in AmpC. The C3(4) carboxylate is recognized by Asn346 and Arg349.…”

Section: Discussionmentioning

confidence: 99%

Structure-Based Approach for Binding Site Identification on AmpC β-Lactamase

2002

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-Lactamases are the most widespread resistance mechanism to -lactam antibiotics and are an increasing menace to public health. Several -lactamase structures have been determined, making this enzyme an attractive target for structure-based drug design. To facilitate inhibitor design for the class C -lactamase AmpC, binding site "hot spots" on the enzyme were identified using experimental and computational approaches. Experimentally, X-ray crystal structures of AmpC in complexes with four boronic acid inhibitors and a higher resolution (1.72 Å) native apo structure were determined. Along with previously determined structures of AmpC in complexes with five other boronic acid inhibitors and four -lactams, consensus binding sites were identified. Computationally, the programs GRID, MCSS, and X-SITE were used to predict potential binding site hot spots on AmpC. Several consensus binding sites were identified from the crystal structures. An amide recognition site was identified by the interaction between the carbonyl oxygen in the R1 side chain of -lactams and the atom Nδ2 of the conserved Asn152. Surprisingly, this site also recognizes the aryl rings of arylboronic acids, appearing to form quadrupole-dipole interactions with Asn152. The highly conserved "oxyanion" hole defines a site that recognizes both carbonyl and hydroxyl groups. A hydroxyl binding site was identified by the O2 hydroxyl in the boronic acids, which hydrogen bonds with Tyr150 and a conserved water. A hydrophobic site is formed by Leu119 and Leu293. A carboxylate binding site was identified by the ubiquitous C3(4) carboxylate of the -lactams, which interacts with Asn346 and Arg349. Four water sites were identified by ordered waters observed in most of the structures; these waters form extensive hydrogen-bonding networks with AmpC and occasionally the ligand. Predictions by the computational programs showed some correlation with the experimentally observed binding sites. Several sites were not predicted, but novel binding sites were suggested. Taken together, a map of binding site hot spots found on AmpC, along with information on the functionality recognized at each site, was constructed. This map may be useful for structure-based inhibitor design against AmpC.

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“…Important amino acid exchanges are T338A in the STMK motif, which leads to a reduced rate of acylation by the ␤-lactam (27,69). In a variant of PBP2x that has a higher affinity for penicillin (40), the active site lies in a deep groove of the protein. In contrast, the flexible architecture of PBP2x from resistant strain SP328 results in an "open" active-site pocket that may be able to accommodate branched peptidoglycan precursors (27), for which it apparently exhibits a substrate preference, as will be discussed below.…”

Section: Structural Characteristics Of Normal and Low-affinity Pbpsmentioning

confidence: 99%

FemABX Peptidyl Transferases: a Link between Branched-Chain Cell Wall Peptide Formation and β-Lactam Resistance in Gram-Positive Cocci

Rohrer

Berger‐Bächi

2003

Antimicrob Agents Chemother

106

102

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The crystal structure of the penicillin-binding protein 2x from Streptococcus pneumoniae and its acyl-enzyme form: implication in drug resistance 1 1Edited by R. Huber

Cited by 202 publications

References 42 publications

The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape

The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape

Structure-Based Approach for Binding Site Identification on AmpC β-Lactamase

FemABX Peptidyl Transferases: a Link between Branched-Chain Cell Wall Peptide Formation and β-Lactam Resistance in Gram-Positive Cocci

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